The goal of this project is to use a combination of genetically engineered mice and virus-mediated gene transfer in conjunction with mouse behavioral tests of learning and memory to identify the neural circuits that may underlie the cognitive decline in PD patients. We will develop two novel transgenic mouse lines that will allow us either to block genetically the production of dopamine in discrete dopaminergic projection regions by viral-mediated recombination of the tyrosine hydroxylase gene or to ablate completely dopamine neurons. We will determine whether the loss of dopamine signaling (by inactivation of tyrosine hydroxylase) or dopamine neuron death (by action of diphtheria toxin) leads to cognitive impairment and morphological changes within the striatum and/or prefrontal cortex (in conjunction with project 2).